Polyneuropathies
Polyneuropathies
What Do You Need to Know?
- GBS: acute ascending paralysis, albuminocytological dissociation, sural sparing on NCS; treat with IVIg or PE — NOT steroids; monitor for respiratory failure (20/30/40 rule)
- CIDP: chronic (>8 weeks) proximal + distal symmetric weakness with demyelinating NCS; unlike GBS, steroids DO work (along with IVIg and PE)
- CMT1A (PMP22 duplication) is the most common hereditary neuropathy — uniform slowing without conduction block distinguishes hereditary from acquired demyelinating neuropathies
- Diabetic neuropathy: distal symmetric polyneuropathy is most common; diabetic amyotrophy = lumbosacral radiculoplexopathy; pupil-sparing CN III = diabetic mononeuropathy
- Small fiber neuropathy: burning pain, normal NCS, diagnose with skin punch biopsy (reduced IENFD)
- Vasculitic neuropathy: mononeuritis multiplex pattern; sural nerve biopsy shows necrotizing vasculitis; treat with steroids + cyclophosphamide
- POEMS syndrome: Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes — always IgA or IgG lambda; look for sclerotic bone lesions
Classification Framework
Approach to Polyneuropathies
| Axis | Categories | Key Examples |
|---|---|---|
| Fiber type | Axonal vs Demyelinating | Axonal: DM, toxic, vasculitic; Demyelinating: GBS, CIDP, CMT1 |
| Time course | Acute (<4 wks), Subacute (4–8 wks), Chronic (>8 wks) | Acute: GBS; Chronic: CIDP, CMT |
| Modality | Motor, Sensory, Sensorimotor, Autonomic | Motor: GBS, MMN; Sensory: B12, cisplatin; Autonomic: DM, amyloid |
| Distribution | Symmetric distal > proximal, Proximal + distal, Asymmetric | Symmetric: DM, CMT; Proximal: CIDP, GBS; Asymmetric: vasculitis, MMN |
| Etiology | Acquired vs Hereditary | Acquired: immune, toxic, metabolic; Hereditary: CMT, HNPP, FAP |
Axonal vs Demyelinating NCS Features
| Feature | Axonal | Demyelinating |
|---|---|---|
| CMAP/SNAP amplitudes | Reduced (primary finding) | May be reduced (secondary to conduction block) |
| Conduction velocity | Normal or mildly slow (>70% LLN) | Markedly slow (<70% LLN) |
| Distal latencies | Normal or mildly prolonged | Prolonged (>130% ULN) |
| F-wave latencies | Normal or mildly prolonged | Prolonged or absent |
| Conduction block | Absent | Present (acquired > hereditary) |
| Temporal dispersion | Absent | Present (acquired demyelination) |
| EMG | Fibrillations, positive sharp waves, neurogenic MUAPs | Usually normal unless secondary axonal loss |
💎 Board Pearl
- Conduction block + temporal dispersion = acquired demyelination (CIDP, GBS, MMN) — hereditary demyelinating neuropathies (CMT1) show uniform slowing WITHOUT conduction block
- If NCS shows reduced amplitudes with relatively preserved velocities → think axonal; if velocities are markedly slow with conduction block → think acquired demyelinating
Guillain-Barré Syndrome (GBS)
GBS Subtypes
| Subtype | Pathology | NCS Pattern | Antibody | Key Features |
|---|---|---|---|---|
| AIDP | Demyelinating (most common in West) | Demyelinating: prolonged DL, slow CV, conduction block, temporal dispersion | None specific | Classic ascending weakness, areflexia; most common subtype overall in US/Europe |
| AMAN | Axonal — motor only | Reduced CMAPs, normal SNAPs, normal CV | Anti-GM1, anti-GD1a | Strong Campylobacter link; more common in Asia; rapid onset, may recover quickly |
| AMSAN | Axonal — motor + sensory | Reduced CMAPs AND SNAPs | Anti-GM1, anti-GD1a | Severe; worse prognosis than AMAN |
| Miller Fisher | Demyelinating variant | Often normal or mild changes | Anti-GQ1b (>90%) | Triad: ophthalmoplegia + ataxia + areflexia; no limb weakness; overlap with Bickerstaff encephalitis (adds altered consciousness) |
Clinical Features & Diagnosis
- Preceding infection: 2/3 of cases; Campylobacter jejuni is most common (30%) — associated with AMAN & anti-GM1; also CMV, EBV, Mycoplasma, Zika, COVID
- Classic presentation: ascending symmetric weakness + areflexia over days to 4 weeks; nadir by 4 weeks (if >8 weeks → consider CIDP)
- Facial weakness: bilateral in ~50%; back pain and neuropathic pain are common early symptoms
- Autonomic dysfunction: tachycardia, bradycardia, BP lability, urinary retention, ileus — leading cause of death in ICU
- CSF: albuminocytological dissociation — elevated protein with normal cell count (≤5 cells/μL); may be normal in first week
- If CSF WBC >50 → think HIV, Lyme, sarcoid, CMV polyradiculopathy, carcinomatous meningitis
Electrodiagnostic Findings
- Earliest finding: absent or prolonged H-reflexes and F-waves (most sensitive in week 1)
- Sural sparing pattern: absent or reduced upper extremity SNAPs with preserved sural SNAP — highly specific for AIDP
- NCS may be normal in the first 1–2 weeks; repeat at 2–3 weeks if initial study is normal
- AIDP: prolonged distal latencies, slow CV, conduction block, temporal dispersion, prolonged F-waves
- AMAN: low CMAPs, normal SNAPs, normal velocities — early reversible conduction failure may mimic demyelination
Respiratory Monitoring — The 20/30/40 Rule
| Parameter | Intubation Threshold | Normal Value |
|---|---|---|
| FVC | <20 mL/kg (or <1 L) | ~65 mL/kg |
| NIF (MIP) | Weaker than −30 cmH2O | −80 cmH2O |
| MEP | <40 cmH2O | >80 cmH2O |
- Erasmus GBS Respiratory Insufficiency Score (EGRIS): predicts need for mechanical ventilation using onset-to-admission interval, facial/bulbar weakness, and MRC sum score
- Monitor FVC every 4–6 hours in progressive GBS; do NOT rely on oxygen saturation (late finding)
Treatment
| Treatment | Details |
|---|---|
| IVIg | 0.4 g/kg/day × 5 days; equivalent to PE; preferred in hemodynamically unstable patients |
| Plasma Exchange (PE) | 5 exchanges over 7–14 days; most effective if started within 7 days of onset |
| Steroids | NOT effective in GBS — do not use alone or in combination with IVIg |
| IVIg + PE combination | NOT superior to either alone — do not combine |
Poor Prognostic Factors
- Age >60, preceding Campylobacter infection, rapid onset (<7 days to unable to walk)
- Need for mechanical ventilation, low CMAP amplitudes (axonal damage), AMAN/AMSAN subtype
- High modified Erasmus GBS Outcome Score (mEGOS) at day 7
- ~5% mortality even with treatment; ~20% still unable to walk at 6 months
💎 Board Pearl
- Anti-GQ1b = Miller Fisher syndrome — the most tested antibody association in GBS
- Anti-GM1 = AMAN — associated with preceding Campylobacter infection and molecular mimicry with gangliosides on motor axon
- Steroids do NOT work in GBS — this is a favorite board distractor (they DO work in CIDP)
- Sural sparing pattern = normal sural SNAP with absent/reduced median or ulnar SNAPs — classic for AIDP
- GBS nadir is by 4 weeks; if still progressing at 8 weeks → reclassify as CIDP (acute-onset CIDP)
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Diagnostic Criteria
- Timeline: progressive or relapsing course >8 weeks (vs GBS which peaks by 4 weeks)
- Pattern: symmetric proximal AND distal weakness (proximal involvement distinguishes from most other neuropathies)
- Reflexes: absent or reduced in all limbs
- CSF: elevated protein (usually >45 mg/dL); WBC ≤10/μL
- NCS (must meet criteria): multifocal demyelination with at least 2 of: prolonged distal motor latencies, slow CV, prolonged F-waves, conduction block, temporal dispersion — in ≥2 nerves
- Nerve biopsy: onion bulb formation (concentric Schwann cell layers from repeated de/remyelination); not required for diagnosis but supportive
CIDP vs GBS
| Feature | GBS | CIDP |
|---|---|---|
| Time course | Acute; nadir ≤4 weeks | Chronic; >8 weeks progressive or relapsing |
| Preceding infection | Common (2/3) | Uncommon |
| Steroids | NOT effective | Effective |
| IVIg | Effective | Effective |
| PE | Effective | Effective |
| Relapse after IVIg | Occurs in ~10% | Common — requires chronic therapy |
| Prognosis | Monophasic; most recover | Chronic; treatment-dependent; >90% respond to first-line therapy |
CIDP Variants
| Variant | Key Features | Notes |
|---|---|---|
| Typical CIDP | Symmetric proximal + distal, motor > sensory | Most common; responds to steroids/IVIg/PE |
| DADS | Distal acquired demyelinating symmetric neuropathy; sensory > motor | Often associated with IgM anti-MAG MGUS; poor response to steroids/IVIg; responds to rituximab |
| MADSAM (Lewis-Sumner) | Multifocal acquired demyelinating sensory and motor; asymmetric | Can mimic MMN; conduction block + sensory involvement; responds to IVIg (steroids may also work) |
| Motor-predominant CIDP | Proximal + distal motor weakness without sensory loss | Must differentiate from MMN; CIDP has proximal weakness, MMN does not |
| Sensory-predominant CIDP | Sensory ataxia, large fiber sensory loss | NCS shows demyelinating features despite predominantly sensory symptoms |
Treatment
- First-line: IVIg (2 g/kg over 2–5 days, then 1 g/kg maintenance every 3–4 weeks), corticosteroids, or PE
- Key difference from GBS: steroids are effective and are first-line for CIDP
- Second-line: azathioprine, mycophenolate, cyclosporine, rituximab
- Subcutaneous Ig (SCIg): alternative to IVIg for maintenance; fewer systemic side effects
- >90% respond to at least one first-line agent; ~50% require long-term immunotherapy
🎯 Clinical Pearl
- DADS + anti-MAG IgM: think MGUS/Waldenström — responds poorly to IVIg and steroids; rituximab is preferred
- If a patient with “CIDP” does not respond to any treatment → reconsider diagnosis: CMT, POEMS, amyloidosis, or CIDP mimic
- Anti-NF155 and anti-CNTN1 antibodies: nodal/paranodal antibodies seen in treatment-refractory CIDP variants; associated with tremor and poor IVIg response; may respond to rituximab
💎 Board Pearl
- Steroids work in CIDP but NOT in GBS — the single most tested fact distinguishing these two
- GBS that is still progressing at 8 weeks = acute-onset CIDP — reclassify and start steroids
- MADSAM (Lewis-Sumner) mimics MMN — but MADSAM has sensory involvement and may respond to steroids; MMN does not
Diabetic Neuropathies
Classification of Diabetic Neuropathies
| Type | Pattern | Key Features |
|---|---|---|
| Distal symmetric polyneuropathy (DSPN) | Length-dependent, sensory > motor | Most common (75%); stocking-glove numbness/pain; small fiber → large fiber progression; loss of ankle jerks first |
| Autonomic neuropathy | Cardiovascular, GI, GU, sudomotor | Orthostatic hypotension, gastroparesis, erectile dysfunction, resting tachycardia; loss of HR variability on ECG |
| Diabetic amyotrophy | Lumbosacral radiculoplexopathy | Acute/subacute proximal leg pain & weakness (thigh); weight loss; may be autoimmune; often unilateral then bilateral; EMG: active denervation in paraspinals + proximal leg muscles |
| Cranial mononeuropathy | CN III most common | Pupil-sparing CN III palsy = diabetic (vasa nervorum ischemia of central fibers; peripheral parasympathetic fibers spared); vs PCA aneurysm = pupil-involving |
| Entrapment neuropathies | Median (CTS), ulnar, peroneal | 2× more common in diabetics; carpal tunnel is most frequent |
| Diabetic thoracic radiculopathy | Thoracic dermatome pain | Unilateral trunk pain; mimics abdominal/cardiac pathology; self-limited |
Small Fiber vs Large Fiber Neuropathy
| Feature | Small Fiber (Aδ, C) | Large Fiber (Aα, Aβ) |
|---|---|---|
| Symptoms | Burning pain, allodynia, autonomic dysfunction | Numbness, tingling, imbalance, weakness |
| Sensory modalities | Pain, temperature | Vibration, proprioception, light touch |
| NCS | Normal | Abnormal (reduced amplitudes) |
| Reflexes | Preserved | Reduced/absent |
| Diagnosis | Skin punch biopsy (IENFD), QSART, autonomic testing | Standard NCS/EMG |
| Gait | Normal | Sensory ataxia (positive Romberg) |
💎 Board Pearl
- Pupil-sparing CN III palsy = diabetes (microvascular ischemia); pupil-involving CN III palsy = PCA aneurysm until proven otherwise
- Diabetic amyotrophy: think of it when a diabetic patient presents with acute painful proximal leg weakness and weight loss — may improve with immunotherapy (IVIg, steroids)
- Tight glycemic control prevents neuropathy in T1DM (DCCT trial) but shows only modest benefit in T2DM (ACCORD)
Hereditary Neuropathies (CMT)
Charcot-Marie-Tooth Classification
| Type | Gene/Protein | Inheritance | Pathology | Key Features |
|---|---|---|---|---|
| CMT1A | PMP22 duplication (17p11.2) | AD | Demyelinating | Most common CMT (~50%); uniform CV slowing (15–25 m/s); onion bulbs; onset 1st–2nd decade; pes cavus, hammertoes, stork legs |
| CMT1B | MPZ (myelin protein zero) | AD | Demyelinating | More severe than CMT1A; severe slowing (<15 m/s); can present as infantile or late-onset forms |
| CMT2A | MFN2 (mitofusin 2) | AD | Axonal | Most common axonal CMT; normal or near-normal CV; reduced CMAP amplitudes; optic atrophy in some |
| CMT-X1 | GJB1 (Connexin 32) | X-linked dominant | Mixed (axonal + demyelinating) | 2nd most common CMT overall; males more severe; females variably affected; intermediate CV (25–40 m/s); CNS white matter changes possible |
| CMT4 | Multiple genes | AR | Demyelinating | Severe, early onset; consanguinity; multiple subtypes |
HNPP and Dejerine-Sottas
| Condition | Genetics | Key Features |
|---|---|---|
| HNPP | PMP22 deletion (vs CMT1A = duplication) | Hereditary neuropathy with liability to pressure palsies; recurrent painless mononeuropathies at compression sites; tomaculous neuropathy (sausage-shaped myelin thickening on biopsy); mild background neuropathy |
| Dejerine-Sottas (CMT3) | PMP22, MPZ, or EGR2 mutations | Severe infantile demyelinating neuropathy; very slow CV (<10 m/s); hypotonia, delayed motor milestones; markedly enlarged nerves; onion bulbs |
Hereditary vs Acquired Demyelination
| Feature | Hereditary (CMT1) | Acquired (CIDP, GBS) |
|---|---|---|
| CV slowing pattern | Uniform across all nerves | Segmental/multifocal |
| Conduction block | Absent | Present |
| Temporal dispersion | Absent | Present |
| CSF protein | Normal or mildly elevated | Elevated |
| Onset | Childhood/adolescence; slowly progressive | Adult; subacute or relapsing |
| Physical exam | Pes cavus, hammertoes, palpable nerves | No skeletal deformities |
💎 Board Pearl
- CMT1A = PMP22 duplication; HNPP = PMP22 deletion — reciprocal unequal crossover on chromosome 17
- Uniform slowing without conduction block = hereditary; segmental slowing WITH conduction block = acquired — this distinction is a board staple
- Pes cavus + hammertoes + areflexia + high steppage gait in a young patient = think CMT
- CMT-X1: only CMT with possible CNS involvement (white matter lesions, transient stroke-like episodes)
Small Fiber Neuropathy
Overview
- Definition: selective involvement of small myelinated (Aδ) and unmyelinated (C) fibers
- Symptoms: burning/stinging pain (feet > hands), allodynia, hyperalgesia; autonomic features (dry eyes/mouth, GI dysmotility, orthostatic intolerance, sweating abnormalities)
- Exam: reduced pinprick and temperature sensation in stocking distribution; preserved vibration, proprioception, and reflexes; strength normal
- NCS/EMG: completely normal (standard NCS only tests large fibers)
Diagnosis
| Test | Finding |
|---|---|
| Skin punch biopsy | Gold standard — reduced intraepidermal nerve fiber density (IENFD) at distal leg (≤3 mm proximal to ankle); age- and sex-matched norms |
| QSART | Quantitative sudomotor axon reflex test — evaluates postganglionic sympathetic sudomotor function |
| Autonomic testing | Tilt table, HR variability, thermoregulatory sweat test |
| Corneal confocal microscopy | Reduced corneal nerve fiber density; noninvasive but limited availability |
Etiologies
| Category | Causes |
|---|---|
| Metabolic | Diabetes/prediabetes (most common), hypothyroidism, uremia |
| Autoimmune | Sjögren syndrome, sarcoidosis, celiac disease, lupus |
| Genetic | Fabry disease (α-galactosidase A deficiency), hereditary sensory/autonomic neuropathies (HSAN), SCN9A/SCN10A channelopathies |
| Infectious | HIV, hepatitis C |
| Toxic | Alcohol, chemotherapy |
| Amyloid | AL amyloidosis, hereditary transthyretin amyloidosis (hATTR) |
| Idiopathic | ~50% remain idiopathic |
💎 Board Pearl
- Normal NCS + burning pain in feet = small fiber neuropathy — order skin punch biopsy
- Fabry disease: X-linked; burning pain in hands/feet in childhood + angiokeratomas + corneal verticillata + renal failure; deficient α-galactosidase A; treatable with enzyme replacement
- If a young patient has unexplained small fiber neuropathy → always check for Fabry, Sjögren (anti-SSA/SSB), and sarcoid (ACE, chest imaging)
Toxic & Metabolic Neuropathies
Drug-Induced Neuropathies
| Drug | Type | Key Features |
|---|---|---|
| Vincristine | Axonal (sensorimotor) | Most common chemo neuropathy; dose-limiting; disrupts microtubules → axonal transport; can cause autonomic neuropathy |
| Cisplatin | Sensory neuronopathy (DRG) | Pure sensory; large fiber > small fiber; affects DRG directly; coasting phenomenon (worsens after stopping) |
| Paclitaxel/Docetaxel | Sensory > motor axonal | Microtubule stabilizers; dose-dependent; stocking-glove pattern |
| Amiodarone | Demyelinating | Mimics CIDP on NCS; also causes optic neuropathy; lysosomal inclusions on biopsy |
| Isoniazid | Axonal sensory | Interferes with pyridoxine (B6) metabolism; prevent with B6 supplementation |
| Nitrofurantoin | Axonal sensorimotor | Worse with renal failure (drug accumulation); contraindicated if CrCl <30 |
| Metronidazole | Sensory axonal | Cumulative dose-dependent; can also cause CNS toxicity (cerebellar) |
| Phenytoin | Mild axonal sensory | Chronic use; usually mild and subclinical |
| Pyridoxine (B6) | Sensory neuronopathy | Megadoses (>200 mg/day) cause neuropathy — paradox: both deficiency AND excess cause neuropathy |
| Dapsone | Motor axonal | Pure motor neuropathy — unusual; used for leprosy/dermatitis herpetiformis |
Heavy Metal Neuropathies
| Metal | Pattern | Classic Clue |
|---|---|---|
| Arsenic | Painful sensorimotor axonal neuropathy | Mees’ lines (transverse white nail bands); GI symptoms first; abdominal pain; hair/nail analysis for chronic exposure |
| Thallium | Painful sensory → motor | Alopecia (within 2–3 weeks); GI symptoms; formerly in rat poison |
| Lead | Motor neuropathy (radial > peroneal) | Wristdrop/footdrop; lead lines on gingiva; basophilic stippling; encephalopathy in children; motor-predominant (unusual for toxic neuropathies) |
| Mercury | Sensory > motor | Organic mercury: CNS predominant (Minamata disease); inorganic: peripheral neuropathy + tremor + erethism |
Nutritional & Metabolic Neuropathies
| Deficiency/Condition | Neuropathy Pattern | Key Features |
|---|---|---|
| Vitamin B12 | Large fiber sensory > motor; subacute combined degeneration | Dorsal columns + corticospinal tracts; elevated methylmalonic acid (most sensitive) and homocysteine; B12 may be borderline normal with elevated MMA; macrocytic anemia may be absent |
| Copper deficiency | Mimics B12 deficiency (myeloneuropathy) | Dorsal column > corticospinal; zinc excess (denture cream) is a common cause; check serum copper + ceruloplasmin |
| Thiamine (B1) | Painful axonal sensorimotor | Beriberi (dry = neuropathy, wet = cardiac); alcohol, malnutrition, bariatric surgery |
| Vitamin E | Spinocerebellar + posterior column | Mimics Friedreich ataxia; fat malabsorption; ataxia + areflexia + proprioceptive loss |
| Alcohol | Distal symmetric axonal sensorimotor | Direct toxicity + thiamine deficiency; painful; most common toxic neuropathy |
| Uremic neuropathy | Distal symmetric axonal sensorimotor | Correlates with GFR; improves with dialysis/transplant; restless legs common |
💎 Board Pearl
- Arsenic = Mees’ lines; Thallium = alopecia; Lead = wristdrop — classic board associations
- Lead is motor-predominant — virtually all other toxic neuropathies are sensory-predominant or mixed
- B6 (pyridoxine): both deficiency (isoniazid) AND excess (>200 mg/day) cause neuropathy — a favorite board question
- Amiodarone neuropathy mimics CIDP (demyelinating pattern) — one of the few drug-induced demyelinating neuropathies
- Subacute combined degeneration + neuropathy: think B12 first, then copper deficiency — check methylmalonic acid
Vasculitic Neuropathy
Overview
- Pattern: mononeuritis multiplex (asymmetric involvement of individual named nerves) that may evolve into confluent distal symmetric pattern
- Mechanism: necrotizing vasculitis of vasa nervorum → ischemic axonal damage
- NCS/EMG: multifocal axonal neuropathy; asymmetric SNAP/CMAP reductions in individual nerve territories
- Diagnosis: sural nerve biopsy — epineurial necrotizing vasculitis with transmural inflammatory infiltrate and fibrinoid necrosis
Causes of Vasculitic Neuropathy
| Category | Conditions | Key Points |
|---|---|---|
| Primary systemic vasculitis | Polyarteritis nodosa (PAN) | Most common vasculitis causing neuropathy; hepatitis B association; medium vessel; affects up to 75% of PAN patients |
| Granulomatosis with polyangiitis (GPA/Wegener) | c-ANCA (anti-PR3); upper/lower respiratory + renal; neuropathy in ~40% | |
| Eosinophilic granulomatosis (Churg-Strauss/EGPA) | p-ANCA (anti-MPO); asthma + eosinophilia + neuropathy; mononeuritis multiplex is most common neuro manifestation | |
| Microscopic polyangiitis | p-ANCA; renal + pulmonary hemorrhage; small vessel | |
| Connective tissue diseases | Rheumatoid arthritis, SLE, Sjögren syndrome | Sjögren: sensory neuronopathy (ganglionopathy) or small fiber neuropathy; SLE: rarely vasculitic |
| Non-systemic vasculitic neuropathy (NSVN) | Confined to PNS | Diagnosis of exclusion; no systemic markers; requires nerve biopsy; better prognosis than systemic; ~50% of all vasculitic neuropathies |
| Infections | Hepatitis B (PAN), Hepatitis C (cryoglobulinemia), HIV | Hep C + cryoglobulinemia → palpable purpura + neuropathy + GN |
Treatment
- Systemic vasculitis: high-dose corticosteroids + cyclophosphamide for induction; azathioprine or methotrexate for maintenance
- NSVN: corticosteroids alone may suffice; add cyclophosphamide if progressive
- Rituximab: increasingly used as alternative to cyclophosphamide in ANCA-associated vasculitis (RAVE and RITUXVAS trials)
💎 Board Pearl
- Mononeuritis multiplex = vasculitis until proven otherwise — also consider diabetes, sarcoid, leprosy, HIV
- PAN: hepatitis B, medium vessel, no glomerulonephritis (vs MPA which has GN), ANCA-negative, most common vasculitis causing neuropathy
- Churg-Strauss/EGPA = asthma + eosinophilia + mononeuritis multiplex — neuropathy in >70%
- Sural nerve biopsy: gold standard for vasculitic neuropathy diagnosis; look for transmural fibrinoid necrosis
Paraproteinemic Neuropathies
Overview
| Condition | Paraprotein | Neuropathy Pattern | Key Features |
|---|---|---|---|
| IgM MGUS with anti-MAG | IgM kappa | Distal demyelinating sensory > motor (DADS pattern) | ~50% of IgM MGUS neuropathies have anti-MAG; widened myelin lamellae on biopsy; tremor and sensory ataxia; poor response to IVIg/steroids; rituximab preferred |
| IgG/IgA MGUS | IgG or IgA | Axonal sensorimotor | Often clinically indistinguishable from idiopathic axonal neuropathy; CIDP-like pattern in some |
| POEMS syndrome | IgG or IgA lambda (>95%) | Demyelinating, motor-predominant | See mnemonic below; sclerotic bone lesions; elevated VEGF; treat underlying plasma cell neoplasm |
| Waldenström macroglobulinemia | IgM | Demyelinating or axonal | Lymphoplasmacytic lymphoma; hyperviscosity; anti-MAG common; may present identical to IgM MGUS neuropathy |
| AL Amyloidosis | Light chains (lambda > kappa) | Small fiber → mixed axonal | Painful small fiber neuropathy + autonomic; carpal tunnel (bilateral); organ infiltration (heart, kidney); Congo red birefringence |
| Multiple myeloma | Various | Axonal sensorimotor | Neuropathy in ~5%; also from amyloid deposition or treatment (bortezomib, thalidomide) |
POEMS Syndrome
- Polyneuropathy — demyelinating, motor ≥ sensory; mandatory criterion; mimics CIDP but does NOT respond to IVIg
- Organomegaly — hepatosplenomegaly, lymphadenopathy
- Endocrinopathy — hypogonadism, hypothyroidism, adrenal insufficiency, diabetes
- M-protein — always IgA or IgG lambda light chain (>95%); kappa is virtually never seen
- Skin changes — hyperpigmentation, hypertrichosis, hemangiomas, white nails
- Other features: elevated VEGF (best marker for disease activity), papilledema, edema/ascites/pleural effusion, thrombocytosis, polycythemia
- Sclerotic bone lesions: osteosclerotic (vs lytic in myeloma) — FDG-PET or whole-body CT for screening
- Treatment: radiation if solitary plasmacytoma; autologous stem cell transplant if disseminated
💎 Board Pearl
- Anti-MAG + IgM MGUS = DADS neuropathy (distal, demyelinating, sensory-predominant) — responds to rituximab, NOT IVIg/steroids
- POEMS = always lambda light chain — if you see kappa, it is NOT POEMS
- POEMS mimics CIDP but does not respond to standard CIDP treatments — check VEGF, SPEP, bone survey
- AL amyloid neuropathy: bilateral carpal tunnel + painful small fiber neuropathy + autonomic failure + cardiac/renal involvement → Congo red biopsy
- Sclerotic vs lytic bone lesions: POEMS = sclerotic; myeloma = lytic — classic board distinction
Critical Illness Polyneuropathy & Myopathy
Critical Illness Polyneuropathy (CIP) vs Critical Illness Myopathy (CIM)
| Feature | CIP | CIM |
|---|---|---|
| Pathology | Axonal neuropathy | Thick filament (myosin) loss myopathy |
| Risk factors | Sepsis, MODS, ICU >1 week | Steroids + NMB agents, sepsis, ICU >1 week |
| Weakness pattern | Diffuse; motor > sensory | Diffuse; proximal ≥ distal |
| Sensory involvement | Yes (reduced pain/temperature) | No |
| Reflexes | Reduced or absent | Reduced (less than CIP) |
| CMAPs | Reduced amplitudes | Reduced amplitudes |
| SNAPs | Reduced (key differentiator) | Normal |
| NCS velocities | Normal or mildly slow (axonal) | Normal |
| EMG (if cooperative) | Fibrillations + neurogenic MUAPs | Fibrillations + myopathic MUAPs (short, small, polyphasic) |
| Direct muscle stimulation | Normal muscle excitability | Reduced muscle excitability (distinguishes CIM from CIP when patient cannot cooperate) |
| CK | Normal or mildly elevated | May be elevated (but often normal) |
| Prognosis | Slower recovery; worse if axonal damage severe | Better prognosis; faster recovery than CIP |
Key Diagnostic Points
- Presentation: difficulty weaning from ventilator + diffuse limb weakness in a septic ICU patient → think CIP/CIM
- Most sensitive early NCS finding: reduced CMAP amplitudes (both CIP and CIM)
- Key distinguishing test: SNAPs — reduced in CIP, preserved in CIM
- Combined CIP/CIM (CIPNM): most patients have overlap; reduced CMAPs + reduced SNAPs + myopathic EMG
- Treatment: no specific therapy; treat underlying sepsis/organ failure; minimize steroids and NMB agents; early mobilization; supportive care
- Prevention: tight glycemic control (van den Berghe trial), early mobilization, minimize sedation
💎 Board Pearl
- CIP vs CIM on NCS: SNAPs are reduced in CIP but preserved in CIM — the single most important distinguishing feature
- CIM has better prognosis than CIP — important for counseling families
- Difficulty weaning + flaccid quadriparesis in ICU → CIP/CIM until proven otherwise; DDx includes prolonged NMB, GBS, spinal cord lesion
- Both CIP and CIM show fibrillation potentials on EMG — fibrillations are NOT specific to denervation (also seen in myopathy)